PROJECT SUMMARY Cognitive decline and deterioration of long-term cognitive performance are major side effects of CNS cancer treatment. Brain metastases are the most common CNS malignancies and a common cause of morbidity and mortality in about 40% of all cancer patients with systemic disease, affecting over 170,000 patients in the US annually. As most systemic chemotherapy agents do not cross the blood brain barrier, the main treatment modalities for brain metastases include surgery, whole brain radiation therapy (WBRT)) and/or stereotactic radiosurgery. The multidisciplinary management of brain metastases aims to achieve durable tumor control within the brain without compromising neurocognitive functioning. However, current results are disappointing. Despite the advantages of WBRT for disease control, cognitive impairment can be seen as early as 3 to 4 months after WBRT, and affects approximately 80-90% of patients, with memory and executive function being the major cognitive domains affected. Abnormal levels of proinflammatory cytokines (PIC) induced in response to ionizing radiation have been proposed as a potential mechanism underlying WBRT-induced cognitive impairment. Shortly after radiation treatment of a tissue, a cascade of cytokines and chemokines is initiated and these mediators perpetuate and augment the inflammatory response for long periods of time, leading to chronic inflammation and tissue injury. MW151 is an orally active, small molecule drug candidate that restores injury- or disease-induced dysregulation of PIC production towards homeostasis without immunosuppression. MW151 selectively attenuates the PIC cascade that occurs in a diverse array of animal models, including mitigation of CNS and skin radiation injury even when given days after radiation exposure. Our goal in the proposed clinical feasibility study is to test the hypothesis that plasma PIC levels are stabilized in patients receiving MW151 in the course of WBRT for the treatment of brain metastases and that MW151 treatment can attenuate therapy-induced cognitive dysfunction in these patients. Our specific aims are: Aim 1 ? Preparation for clinical study. Aim 2 ? Recruitment and conduct of the clinical study. Aim 3: Evaluation of clinical study outcomes. This pilot study will provide data regarding the feasibility of the clinical use of MW151 as an adjunct to WBRT, the current standard of care, to reduce the cognitive decline after radiation therapy for patients with brain metastases.